It is critical to identify and characterize factors involved in obesity, so that interventions to prevent or reverse the nutrition-related negative health sequelae of obesity can be developed. To do so requires a better understanding of lean-obese differences in the mechanisms that determine human food intake. The proposed studies represent the first systematic investigation of three important factors involved in the regulation of energy and macronutrient intake in obese and lean females and males. These are: l) the energy content of ingested foods; 2) the volume or weight of ingested foods; and 3) the macronutrient composition of ingested foods. Our approach is to use rigorous laboratory-based procedures to isolate and define variables that affect human caloric and macronutrient intake, and the proposed experiments logically follow from previous work this laboratory has performed examining the determinants of human food intake. These studies will take advantage of new food technologies that have allowed the development of preload meals that can be consumed orally or infused intragastrically, yet do not differ detectably in their sensory properties. The use of intragastric infusions of the same foods that are consumed orally provides a unique tool for dissociating orosensory and cognitive controls (which are important cues particularly for obese individuals) from postingestive physiological controls of energy and macronutrient intake. A dose-response preloading paradigm provides the most sensitive index of satiety, and the three studies in this proposal reflect this design, Specifically, we will test the hypothesis that thresholds relating to energy or volume detection are elevated or absent in obese individuals. We will also test the hypothesis that calorie-for- calorie, energy provided by fat (as compared to carbohydrate) will be less satiating in obese individuals. In all studies we will be comparing the responses of obese and lean individuals to test the predictions that obesity is associated with: I) an impaired regulation of energy intake; 2) a relative insensitivity to energy provided by fat as compared to carbohydrate; and 3) a greater reliance on orosensory/cognitive cues as compared to postingestive influences. Studies like these performed in animals have generated important insights into the contributions of orosensory, gastric, and postgastric stimulation in determining eating behavior, although comparable systematic research has not been conducted in humans, The proposed experiments will provide crucial new information on the respective roles of energy content, the volume or weights of foods, macronutrient composition, and interactions between orosensory and postingestive factors in the regulation of energy and macronutrient intake. This information will be important in forming the foundation for more mechanistic analyses to follow and for the eventual development of interventions to prevent or reverse obesity-related illness.